Adult stem cell defines a stem cell found in a differentiated tissue in an adult organism which may, with certain limitations, differentiate to yield all the specialized cell types of the various tissues. Adult stem cells may be derived from cells of the group consisting of breast, bone marrow, umbilical cord blood, peripheral blood, liver, skin, gastrointestinal tract, placenta, and uterus. Adult stem cells include neuronal stem cells capable of differentiating into neuronal cells, hematopoietic stem cells capable of differentiating into blood cells, mesenchymal stem cells capable of differentiating into bone, cartilage, fat, and muscle, and hepatic stem cells capable of differentiating into hepatocytes.
Among them, hematopoietic stem cells (HSCs) constitute a rare subpopulation in hematopoietic tissues with the ability to give rise to all types of mature blood cells. These hematopoietic stem cells exhibit long-term repopulating activities when transplanted into myeloablated hosts through their unique ability to execute self-renewal during regeneration. The cells are referred to as competitive repopulating units (CRUs), and quantitative increments in these CRU numbers have been the key evidence for self-renewal of hematopoietic stem cells.
On the other hand, Wnt proteins constitute a large family of cysteine-rich secreted ligands, which bind to membrane receptors via an autocrine or paracrine mechanism, and thus activate the Wnt pathway (receptor-mediated signal transduction pathway). In vertebrates, the Wnt signaling pathway functions to regulate organ development, and cellular proliferation, morphology, motility, and fate (Logan, C. Y., and R. Nusse. 2004. 20:781-810). The Wnt signaling pathway is divided into two branches whose differential activation depends on the binding of Wnt proteins to membrane receptors. One is the β-catenin-dependent Wnt pathway, also called canonical Wnt pathway, which is activated by Wnt1, Wnt2, Wnt3a, Wnt10a or the like, regulates cell fate determination, and is involved in cell proliferation or survival. The other is the β-catenin-independent Wnt pathway, also called non-canonical Wnt pathway or Wnt/calcium pathway, which is activated by Wnt4, Wnt5a, and Wnt11, and mediates cell polarity, adhesion, and shape.
In the canonical Wnt pathway, β-catenin is destabilized by a destruction complex composed of Axin, serine-threonine kinase, and glycogen synthase kinase 3β in the absence of Wnt signals. Wnt binding to Frizzled family receptors and LRP5/6 inhibits the formation of a destruction complex, and induces β-catenin stabilization and its entry into the nucleus where it activates TCF/LEF target genes (Wodarz, A., and R. Nusse. 1998. Annu Rev Cell Dev Biol 14:59-88).
There are many studies on the role of β-catenin in the self-renewal of hematopoietic stem cells. In a recent study on mice with conditional inactivation of β-catenin, normal hematopoietic development and repopulating activity were observed, suggesting that β-catenin activity is dispensable for HSC function (Cobas, M., A. et al. 2004. J Exp Med 199:221-229). Furthermore, mice with in vivo stabilized β-catenin exhibited defective hematopoietic repopulation and differentiation during steady-state or stimulated conditions in a myeloablated host (Kirstetter P., et al. 2006. Nat Immunol 7:1037-1047), which were nevertheless accompanied by expansion of phenotypically defined HSCs. Thus, the precise role of β-catenin in hematopoiesis remains unclear.